Anthracyclines form one of the largest families of naturally occurring bioactive compounds. Several members of this family have shown to be clinically effective anti-neoplastic agents. These include, for example, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, aclarubicin, and carminomycin. For instance, these compounds have been shown to be useful in bone marrow transplantation, stem cell transplantation, treatment of breast carcinoma, acute lymphocytic and non-lymphocytic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and other solid neoplasias.
The most common starting material, utilized for synthesis of semi-synthetic derivatives of anthracyclins, is Daunorubicin. In Daunorubicin, the 4′-hydroxyl group of aminoglycoside fragment is in axial configuration. For production of epi-derivatives, it is necessary to change the configuration of this hydroxyl group from axial to equatorial. This can be attained in two ways: oxidation of the 4′-OH group to ketone (with loss of an optical center) with further stereospecific reduction to the required equatorial configuration [1]; or biomolecular nucleophilic substitution of 4′-OTf—derivative, accompanied by Walden inversion and, hence, by epimerization [2]. These modifications can be accomplished both on intact anthracyclin molecules and on isolated aminosugars, derived as a result of algycone removal [3] or separately synthesized [4]. Simplicity of working with isolated aminosugar is countered by difficulty of a stereospecific reaction of aglycone glycosilation. In this situation, more times than not, the real yield of the required α-anomer of anthracyclin appears to be less than those previously declared [3,4,5].
Modification of 14-R2═H to 14-R2═OH is conducted by halogenization of the end methyl group with molecular bromine or iodine at room or lower (6-10° C.) temperature in a mixture of anhydrous methanol and dioxane [6]. Earlier patents described bromination of the unprotected ketone group; afterwards, ketone protection the 13-C═O group was demonstrated [7]. Next, the halogen undergoes nucleophilic substitution with hydroxyl or a carboxylate anion with creation of an intermediate ester 14-R2═OCOAlk (Ar), where, most commonly, R2═OCOH. This ester is then hydrolyzed to 14-R2═OH.
The described methods, especially those that require glycosilation stage, require utilization of a significant number of protection groups in order to provide an adequate modification of anthracyclin molecule. Placement and removal of protection groups significantly increases the number of synthetic stages, and decreases the yield of the product. The subject of the present patent is decrease in the number of stages of the synthetic process and increase in the selectivity of the chemical reactions, including stereospecificity, during synthesis both currently-known and future novel anthracyclins.